To test the hypothesis that in the presence of trauma and sepsis circulating agents, in addition to hormones, may induce certain of the characteristic metabolic abnormalities the alterations of enzyme activity and utilization of substrates in various tissues are being examined. It has been observed in skeletal muscle of rat with induced peritonitis that pyruvate dehydrogenase activity is significantly reduced below that found in starvation, despite the presence of hyperinsulinemia. Furthermore, glycogen deposit in response to insulin is reduced in vitro in the muscle from traumatized and septic rats. Normal muscle tissue incubated with plasma from a septic rat becomes insulin resistant and glycogen deposit is not stimulated as occurs when normal plasma is present. The peripheral metabolism of muscle and adipose tissue, measured by blood flow and arterio-venous differences of substrates and metabolites in the hind limbs of pigs reveals significant alterations to be caused by induced peritonitis. Despite normal glucose and oxygen uptake, fat oxidation is increased and lactate is produced. Preliminary experiments indicate that certain vasoactive peptides and the non-protein fraction of plasma from septic animals and patient may reproduce these changes. In addition to further studies on enzyme activity and substrate utilization of tissues work will be devoted to testing fractions of plasma from normal, post-traumatic, and septic animals and patients using the rat muscle and pig hind limb as bioassay systems. Agents may be defined and possibly identified which alter the metabolism in the characteristic fashion.